P-menthane carboxamides having a physiological cooling effect

ABSTRACT

N-substituted-p-menthane-3-carboxamides are disclosed having the property of stimulating the cold receptors of the nervous system of the human body to produce a cold sensation and are used for this purpose in a variety of edible and topical preparations.

RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No. filedJan. 28, 1972, now abandoned. It is also related to applications Ser.Nos. 486,565 and 486,566.

Field of Invention

This invention relates to compositions and compounds having aphysiological cooling effect on the skin and on the mucous membranes ofthe body, particularly those of the mouth, nose, throat andgastrointestinal tract.

BACKGROUND OF THE INVENTION AND PRIOR ART

Menthol is well known for its physiological cooling effect on the skinand mucous membranes of the mouth and has been extensively used as aflavouring agent (menthol being a major constituent of oil ofpeppermint) in foodstuffs, beverages, dentifrices, mouthwashes, etc. andas a component in a wide range of toiletries, liniments and lotions fortopical application. Menthol is also a well known tobacco additive forproducing a "cool" sensation in the mouth when smoking.

It is well established that the "cooling" effect of menthol is aphysiological effect due to the direct action of menthol on the nerveendings of the human body responsive for the detection of hot or coldand is not due to latent heat of evaporation. It is believed that thementhol acts as a direct stimulus on the cold receptors at the nerveendings which in turn stimulate the central nervous system.

Although menthol is well established as a physiological coolant its use,in some compositions, is circumscribed by its strong minty odour and itsrelative volatility.

A few other compounds have been reported in the technical literature ashaving an odour or flavour similar to menthol and from time to time havebeen proposed as flavourants or odourants in a variety of topical andingestible compositions. For example, Japanese Patent Publication No.39-19627 reports that 3-hydroxymethyl p-menthane (menthyl carbinol) hasa flavour closely resembling that of 1-menthol and suggests its use as aflavourant; in confectionery, chewing gum and tobacco. In Swiss PatentNo. 484,032 certain saccharide esters of menthol are proposed asadditive to tobacco. In French Pat. Spec. No. 1,572,332 N,N-Dimethyl2-ethylbutanamide is reported as having a minty odour and refreshingeffect, and the minty odour of N,N-diethyl 2,2-dimethylpropanamide isreferred to. A similar effect is reported for N,N-diethyl2-ethylbutanamide in Berichte 39, 1223, (1906). A minty odour has alsobeen reported for 2,4,6-trimethylheptan-4-ol and 2,4,6-trimethylhept-2-en-4-ol in Parfums-Cosmetiques-Savons, May 1956, pp. 17-20. Thecooling effect of menthol and other related terpene alcohols and theirderivatives has also been studied and reported in Koryo, 95, (1970), pp.39-43. 2,3-p-menthane diol has also been reported as having a sharpcooling taste (Beilstein, Handbuch der Organischen Chemie, 4th Ed.(1923) Vol. 6, p. 744.).

Despite this knowledge of other compounds having an odour and flavoursimilar to that of menthol, menthol is still extensively used intopical, ingestible and other compositions notwithstanding thedisadvantages mentioned above, namely its very strong odour and itsrelative volatility.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide other compoundshaving a pronounced physiological cooling effect, in many cases far morepersistent than that obtained with menthol, without the attendantdisadvantages of a strong odour.

It is a further object to provide compounds having a pronouncedphysiological cooling effect and being of relatively low volatility.

It is a further object of the present invention to provide ingestible,topical and other compositions capable of stimulating the cold receptorsof the nervous system of the human body thereby to create a desirable"cool" sensation, and a method of making them.

It is a yet further object of the present invention to provide a methodof stimulating the cold receptors of the nervous system of the body tocreate a cool sensation.

Other objects will be apparent from the following detailed descriptionof the invention.

SUMMARY OF THE INVENTION

The present invention is based on the discovery of a group of3-substituted-p-menthanes which have a pronounced physiological coolingactivity, which has little or no odour, which are of relatively lowvolatility and which are substantially non-toxic. These compounds are3-substituted-p-menthanes of the formula: ##STR1## where R', when takenseparately, is hydrogen or an aliphatic radical containing up to 25carbon atoms;

R", when taken separately is hydroxy, or an aliphatic radical containingup to 25 carbon atoms, with the proviso that when R' is hydrogen R" mayalso be an aryl radical of up to 10 carbon atoms and selected from thegroup consisting of substituted phenyl, phenalkyl or substitutedphenalkyl, naphthyl and substituted naphthyl, pyridyl; and

R' and R", when taken together with the nitrogen atom to which they areattached, represent a cyclic or heterocyclic group of up to 25 carbonatoms, e.g. piperidino, morpholino etc.

In the above definitions "aliphatic" is intended to include anystraight-chained, branched-chained or cyclic radical free or aromaticunsaturation, and thus embraces alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, hydroxyalkyl, acyloxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, acylaminoalkyl, carboxyalkyl and similar combinations.

Typical values for R' and R" when aliphatic are methyl, ethyl, propyl,butyl, isobutyl, n-decyl, cyclopropyl, cyclohexyl, cyclopentyl,cycloheptylmethyl, 2-hydroxyethyl, 3-hydroxy-n-propyl,6-hydroxy-n-hexyl, 2-aminoethyl, 2-acetoxyethyl, 2-ethylcarboxyethyl,4-hydroxybut-2-ynyl, carboxymethyl etc.

When R" is aryl typical values are benzyl, naphthyl, 4-methoxyphenyl,4-hydroxyphenyl, 4-methylphenyl, 3-hydroxy-4-methylphenyl,4-fluorophenyl, 4-nitrophenyl, 2-hydroxynaphthyl, pyridyl, etc.

STATEMENT OF INVENTION

In accordance with this invention, therefore, there are providedconsumer products for application to or consumption by the human bodycomprising a consumer product base and a means for stimulating the coldreceptors of the nervous system of the human body wherein said meanscomprise an effective amount of one or more 3-substituted-p-menthanes ofthe formula hereinbefore set forth.

By consumer product we mean a manufactured product applied to orconsumed by the human person for toilet, cosmetic, hygienic, nutritive,curative, prophylactic, or other purposes and constituting a vehicle bymeans of which the said 3-substituted-p-menthane may be brought intocontact with the skin, mucous membranes or other surface tissues of thebody, whether external tissues or internal, for example, of the nose,throat, mouth and gastrointestinal tract, and includes liquid and solidphase preparations of an essentially formless nature e.g. solutions,emulsions, pastes, ointments, powders etc., solid phase preparations ofsemi-permanent form, e.g. shaped toilet and cosmetic preparations andshaped edible preparations, whose shaped form is only temporary andwhich lose that form on use, and articles of permanent form but whichare of an essentially disposable nature, e.g. cleansing tissues,toothpicks etc.

Typical consumer products into which the 3-substituted-p-menthanes maybe incorporated in accordance with this invention and which maytherefore serve as vehicles for application of the compounds to theperson are:

1. Edible and potable compositions including alcoholic and non-alcoholicbeverages; confectionery; chewing gum; cachous; ice cream; jellies;

2. Toiletries including after-shave lotions, shaving soaps, creams andfoams, toilet water, deodorants and antiperspirants, "solid colognes",toilet soaps, bath oils and salts, shampoos, hair oils, talcum powders,face creams, hand creams, sunburn lotions, cleansing tissues,dentifrices, toothpicks, mouthwashes, hair tonics, eyedrops.

3. Medicaments including antispetic ointments, pile ointments,liniments, lotions, decongestants, counter-irritants, cough mixtures,throat lozenges, antacid and indigestion preparations, oral analgesics;

4. Miscellaneous compositions such as water soluble adhesivecompositions for envelopes, postage stamps, adhesive labels etc.

DETAILED DESCRIPTION

The 3-substituted-p-menthanes used as cold receptor stimulants in theconsumer products of this invention may be readily prepared byconventional methods, such as by the reaction of the corresponding acidchloride (obtained by reacting p-menthane-3-carboxylic acid with thionylchloride) with the appropriate mono or di-substituted amine. Thereaction will usually be carried out in solution in the presence of ahydrogen chloride receptor e.g. sodium hydroxide. The reaction proceedssmoothly at room temperature.

The compounds used as cold receptor stimulants in accordance with thisinvention exhibit both geometric and optical isomerism and, depending onthe starting materials and the methods used in their preparation thecompounds may be isomerically pure, i.e. consisting of one geometric oroptical isomer, or they may be isomeric mixtures, both in the geometricand optical sense.

As is well known, the basic p-methane structure is a chair-shapedmolecule which can exist in cis or trans forms. Substitution of thecarboxyl or amide group into the 3-position gives rise to fourconfigurational or geometric isomers depending upon whether thesubstitution is axially or equatorially into the cis or trans isomer,the four isomers being related as menthol is to neomenthol, isomenthol,and neoisomenthol. In general it is found that in the compounds used inthis invention the equatorially substituted derivatives have the greatercooling effect than the axial compounds and are to be preferred.

Substitution of the amide group in the 3-position of the p-menthanestructure also gives rise to optical isomerism, each of theabove-mentioned four geometric isomers, existing in d, l and dl forms.The physiological cooling effect is found, in most cases, to be greaterin the l-form than in d-form, and in some cases substantially greater.The amide derivatives of the l-acid are therefore preferred.

The cooling sensation created by the compounds used in this invention onthe skin and mucous membranes, for example, in the mouth, varies both inintensity and longevity from compound to compound.

When either R' and R" is aliphatic the preferred values are C₁ -C₉straight or branched chain alkyl, C₁ -C₉ straight or branched chainhydroxyalkyl or aminoalkyl and C₁ -C₄ acylated derivatives thereof, and--C_(n) H_(2n) COR'" or --C_(n) H_(2n) COOR'", where --C_(n) H_(2n) is astraight or branched chain alkylene radical in which n is an integer offrom 1-6 and R'" is hydrogen or a C₁ -C₈ alkyl or hydroxyalkyl group,preferably a C₁ -C₄ straight chain alkyl group.

In general the monosubstituted compounds, i.e. where R' is H, arepreferred although di-substituted compounds where R' and R" are both C₁-C₃ alkyl also show a very pronounced cooling effect. Most preferred ofall are compounds where R' is H and R" is C₁ -C₃ alkyl, C₁ -C₄hydroxyalkyl, or --CH₂ COOR'", where R'" is C₁ -C₄ alkyl.

Also included within the scope of this invention are compounds where R'is H and R" is hydroxy or substituted phenyl, e.g. alkylphenyl,hydroxyphenyl, alkoxyphenyl, halophenyl of up to 10 carbon atoms,phenalkyl or substituted phenalkyl e.g. benzyl, naphthyl or substitutednaphthyl, and compounds where R' and R" are joined to form a cyclicgroup. When so joined R' and R" preferably represent an alkylene chain,optionally interrupted by oxygen, which together with the nitrogen atomto which R' and R" are attached forms a 5- or 6-membered heterocyclicring.

For the purposes of the present disclosure the following test procedurehas been devised as a means to identify compounds having a physiologicalcooling activity in accordance with the present invention and hereinreferred to as cold receptor stimulants. This test is intended purely asa means for identifying compounds having a physiological coolingactivity and useful in the present invention and for giving anindication of the different relative activities of the compounds, asbetween themselves and as compared with menthol, when applied in aparticular manner to a particular part of the body. The results are notnecessarily indicative of the activity of these compounds in otherformulations and other parts of the body where other factors come intoplay. For example, a controlling factor in the onset of cooling effect,its intensity and longevity will be the rate of penetration of thecompounds through the epidermis and this will vary in differentlocations on the human body. The formulation of actual productsaccording to this invention will therefore be done largely on anempirical basis although the test results and other figures given hereinwill be useful as a guide, particularly in the formulation of productsfor oral administration, since the test procedure to be describedinvolves oral application of the compound. A similar test may, ofcourse, be devised for the purposes of measuring the relative activitiesof the compounds on another area of the body, for example, the face orforearm, and this will be a useful guide in the choice of compounds tobe used in preparations for external topical usage.

It will also benoted that the described test procedure is done on astatistical basis. This is necessary since sensitivity to thesecompounds will vary not only from compound to compound and from one partof the body to another, but also from one individual to another. Testsof this nature are commonly used in the testing of the organolepticproperties, e.g. taste, smell etc. of organic and inorganic compounds,see Kirk-Othmer: Encyclopedia of Chemical Technology, 2nd. Ed. (1967)Vol. 14 pages 336 - 344

Test Procedure

The following test procedure is aimed at determining the minimumquantity of the test compound required to produce a noticeable coolingeffect on a person of average sensitivity, this minimum quantity beingtermed the threshold for that particular compound. The tests are carriedout on a selected panel of 6 people of median sensitivity to 1-menthol.

Panel Selection

To select a test panel of average sensitivity the following procedure isused. Known quantities of 1-menthol in solution in petroleum ether(bp.40-60) are placed on 5 mm. squares of filter paper, whereafter thesolvent is allowed to evaporate. A panel of observers is enrolled andasked to place one impregnated square at a time on the tongue and toreport on the presence or absence of a cooling effect. The quantity of1-menthol on each impregnated square is gradually reduced from a valuesubstantially above 0.25 μg. per square to substantially below 0.25 μg,the precise range being immaterial. Conveniently, one starts withsquares containing 2.0 μg. 1-menthol, the amount on each successivesquare being half that of the preceding square, i.e. the second testsquare will contain 1.0 μg, the third 0.5 μg and so on. Each quantity istested on the tongue at least 10 times. In this way, the thresholds tocold receptor stimulus by 1-menthol are determined for each individualof the panel, the threshold for each individual being that amount of1-menthol for which, in a series of not less than 10 test applications,a cooling effect is reported 50% of the time. Six panel members are nowselected whose threshold to 1-menthol is in the range 0.1 μg to 10 μgand whose average threshold is approximately 0.25 μg., this select panelbeing regarded as the test panel of average sensitivity.

Compound testing

To test the activity of compounds according to this invention, the aboveprocedure is repeated using only the 6 selected panel members of averagesensitivity to 1-menthol. The individual thresholds for each testcompound on each of the 6 selected panel members are determined andaveraged. Those compounds whose average threshold on the select testpanel is 100 μg or less are regarded as having cooling activity inaccordance with this invention.

Test Results

The following table sets out the relative cooling activities ofcompounds of the formula defined above when tested according to theforegoing procedure.

                                      Table                                       __________________________________________________________________________    Compound                      Threshold                                       __________________________________________________________________________    R'      R"                    μg.                                          H       --CH.sub.3            1.1                                             "       --C.sub.2 H.sub.5     0.3                                             "       --C.sub.3 H.sub.7 (n) 0.8                                             "       --C.sub.3 H.sub.7 (iso)                                                                             0.5                                             "       --C.sub.4 H.sub.9 (n) 1.4                                             "       --C.sub.4 H.sub.9 (iso)                                                                             0.9                                             "       --C.sub.4 H.sub.9 (sec)                                                                             0.7                                             "       --C.sub.4 H.sub.9 (tert.)                                                                           0.4                                             "       --C.sub.5 H.sub.11 (n)                                                                              3                                               "       --C.sub.10 H.sub.21 (n)                                                                             10                                              "       --CH.sub.2 CH.sub.2 OH                                                                              5                                               "       --(CH.sub.2).sub.3 OH 3                                               "       --CH.sub.2 CH(OH)CH.sub.3                                                                           5.5                                             "       --C(CH.sub.3).sub.2 CH.sub.2 OH                                                                     0.4                                             "       --CH.sub.2 C.tbd.CCH.sub.2 OH                                                                       17                                              "       --(CH.sub.2).sub.6 OH 1.0                                             "       --CH(C.sub.2 H.sub.5)CH.sub.2 OH                                                                    1.0                                             "       --CH.sub.2 OH         12                                              "       --CH.sub.2 COOC.sub.3 H.sub.7 (n)                                                                   0.3                                             "       --CH.sub.2 COOC.sub.2 H.sub.5                                                                       0.2                                             "       --CH.sub.2 COOH       16                                              "       --CH(CH.sub.3)COOC.sub.2 H.sub.5                                                                    0.4                                             "       --CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5                                                              1.5                                             "       --CH.sub.2 COOCH.sub.3                                                                              0.6                                             "       --CH(CH.sub.3)CH.sub.2 COOC.sub.2 H.sub.5                                                           0.8                                             "       --CH.sub.2 CH.sub.2 OCOCH.sub.3                                                                     1.5                                             "       --CH.sub.2 CH.sub.2 NH.sub.2                                                                        20                                              --CH.sub.3                                                                            --CH.sub.3            1.5                                             --C.sub.2 H.sub.5                                                                     --C.sub.2 H.sub.5     3                                               --CH.sub.2 CH.sub.2 OH                                                                --CH.sub.2 CH.sub.2 OH                                                                              50                                              --CH.sub.3                                                                            --CH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                                 0.8                                             --CH.sub.3                                                                            --CH.sub.2 CH.sub.2 OH                                                                              5                                               --C.sub.3 H.sub.7 (iso)                                                               --CH.sub.2 CH.sub.2 OH                                                                              3                                               H       --C.sub.3 H.sub.5 (cyclo)                                                                           0.5                                             "       --C.sub.5 H.sub.9 (cyclo)                                                                           0.5                                             "       --C.sub.6 H.sub.11 (cyclo)                                                                          1                                               "       --C.sub.7 H.sub.13 (cyclo)                                                                          3                                               --C.sub.2 H.sub.5                                                                     --C.sub.4 H.sub.9 (iso)                                                                             5                                               H       --CH.sub.2 (C.sub.7 H.sub.13 (cyclo)                                                                20                                              H       --OH                  11                                              --(CH.sub.2 H.sub.4 --        5                                               --(CH.sub.2).sub.5 --         6                                                       --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           5.5                                                     --CH.sub.2 CH.sub.2 NHCH.sub.2 CH.sub.2 --                                                          15                                                      --CH(CH.sub.3)CH.sub.2 CH.sub.2 CH(CH.sub.3)--                                                      0.5                                                     --CH.sub.2 (CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)--                                      2                                                       --CH(CH.sub.3)CH(C.sub.2 H.sub.5)CH.sub.2 C(CH.sub.3)--                       --CH(iso-C.sub.3 H.sub.7)CH.sub.2 CH.sub.2 CH(CH.sub.3)CH.sub.2               CH.sub.2 --           50                                              H       --CH.sub.2 Ph         10                                              "       --C.sub.6 H.sub.4 OMe(p)                                                                            0.1                                             "       --C.sub.6 H.sub.4 OH(p)                                                                             1.4                                                     --C.sub.6 H.sub.4 Me(p)                                                                             0.3                                                     --C.sub.6 H.sub.4 OH(o)                                                                             0.5                                                     --C.sub.6 H.sub.3 Me(p)OH(m)                                                                        0.1                                                     --C.sub.6 H.sub.3 Me.sub.2 (m,p)                                                                    0.1                                                     --C.sub.6 H.sub.4 F(p)                                                                              0.5                                                     --C.sub.6 H.sub.4 NO.sub.2 (p)                                                                      0.3                                                     --3-Pyridyl           0.5                                             __________________________________________________________________________

The cold receptor stimulants used in this invention find utility in awide variety of consumer products for consumption by or application tothe human body. Broadly speaking, these products can be divided intoingestibles and topicals, both terms being taken in their broadestpossible sense. Thus ingestible is to be taken as including not onlyfoodstuffs and beverages taken into the mouth and swallowed, but alsoother orally ingested products taken for reasons other than theirnutritional value, e.g. indigestion tablets, antacid preparations,laxatives, etc. Ingestible is also to be taken to include ediblecompositions taken by mouth, but not necessarily swallowed, e.g. chewinggum. Topical is to be taken as including not only compositions such asperfumes, powders and other toiletries, lotions, liniments, oils andointments, applied to the external surfaces of the human body, whetherfor medical or other reasons, but also compositions applied to, orwhich, in normal usuage, come in contact with, internal mucous membranesof the body, such as those of the nose, mouth, or throat, whether bydirect or indirect application or inhalation, and thus include nasal andthroat sprays, dentifrice, mouthwash and gargle compositions. Topicalproducts, in this context, also include toilet articles such ascleansing tissues and toothpicks.

In formulating the products of this invention the3-substituted-p-menthane will be incorporated into a vehicle by means ofwhich the compound may be applied to the person. The vehicle may, itselfbe completely inert or it may, and usually will, contain other activeingredients. A wide variety of vehicles will be suitable, depending uponthe particular product involved, such vehicles including solids,liquids, emulsions, foams and gels. Typical vehicles for the3-substituted-p-menthane include aqueous or alcoholic solutions, oilsand fats such as hydrocarbon oils, fatty acid esters, long chainalcohols and silicone oils; finely divided solids such as starch ortalc; cellulosic materials such as paper tissue; low-boilinghydrocarbons and halohydrocarbons used as aerosol propellants; gums andnatural or synthetic resins.

Generally, these vehicles will contain at least one or more of thefollowing adjuvants: flavourants, colourants, perfuming agents, surfaceactive agents, antiseptic agents, such as are usually employed intopical and ingestible compositions.

A more detailed discussion of particular products according to thisinvention follows.

Toiletries and Cosmetics

A major area of utility of the 3-substituted-p-menthanes of thisinvention will be in the field of toilet preparations broadly classed aspersonal care products. These may be defined as manufactured productsapplied to the person for the purposes of grooming or hygiene or forcosmetic purposes, including make up and perfumery, but excludingethical and proprietary medical preparations. Particular personal careproducts are discussed hereinafter by way of example and are illustratedhereinafter in the specific examples.

One class of personal care products into which the compounds of thisinvention may be incorporated is represented by lotions for topicalapplication, e.g. after-shave lotions, toilet water etc. where thecompound will be used in alcoholic or aqueous alcoholic solution, suchsolutions usually also containing a perfume or mild antiseptic or both.The amount of compound added to the formulation will usually be in therange 0.1 to 3% by weight based on the total composition.

Another class of personal care product is represented by soap andsoap-based compositions where the compounds will be used in combinationwith an oil or fat or a natural or synthetic surfactant e.e. a fattyacid salt or a lauryl sulphate salt, the composition usually, containingan essential oil or perfume. The range of soap compositions will includesoaps of all kinds e.g. toilet soaps, shaving soaps, shaving foams etc.particularly shaving foams of the aerosol type. Usually the compoundwill be added to the formulation in amount of from 0.5 to 4.0% byweight.

A further class of personal care products into which the3-substituted-p-menthanes may be incorporated is represented by cosmeticcreams, emollients and lotions, such creams, emollients and lotionsusually comprising an oil-in-water emulsion as a base and optionallycontaining a range of other ingredients such as wax, preservative,perfume, antiseptics, astringents, pigments etc. Also included withinthis class are lipstick compositions, such compositions usuallycomprising an oil and wax base into which the coolant can beincorporated along with other ingredients e.g. pigments. Once again theformulations of such products, apart from the incorporation of the3-substituted-p-menthane, usually in an amount of from 0.01 to 5.0% byweight, is conventional.

Personal care products for oral hygiene into which the cold receptorstimulants of this invention can be incorporated include mouthwash,gargle and dentifrice compositions. The first two may be consideredtogether and will usually comprise an aqueous, alcoholic oraqueous-alcoholic solution of an antiseptic often coloured or flavouredfor palatability, to which the 3-substituted-p-menthane is added in anamount of from 0.01 to 0.5% by weight.

Dentifrice compositions may be of the solid block, powder, paste orliquid type and will usually comprise a finely divided abrasive orpolishing material, e.g. precipitated chalk, silica, magnesium silicate,aluminum hydroxide or other similar materials well known in the art, anda detergent or foaming agent. Optional ingredients which may also beincluded are flavouring agents and colourants, antiseptics, lubricants,thickeners, emulsifiers or plasticizers. The amount of3-substitued-p-menthane added in such compositions will generally befrom 0.1 to 1.0% by weight based on the total composition.

EDIBLE AND POTABLE COMPOSITIONS

The 3-substituted-p-menthanes of this invention may be incorporated intoa wide range of edible and potable compositions comprising an edible orpotable base and usually one or more flavouring or colouring agents. Theparticular effect of the 3-substitued-p-menthane is to create a cool orfresh sensation in the mouth, and in some cases, even in the stomach,and therefore the compounds find particular utility in sugar-basedconfectionery such as chocolate, boiled sweets, mints and candy, in icecream and jellies and in chewing gum. The formulation of suchconfections will be by traditional techniques and according toconventional recipes and as such forms no part of this invention. The3-substituted-p-menthane will be added to the recipe at a convenientpoint and in amount sufficient to produce the desired cooling effect inthe final product. As already indicated, the amount will vary dependingupon the particular compound, degree of cooling effect desired and thestrength of other flavourants in the recipe. For general guidance,however, amounts in the range 0.01 to 5.0% by weight based on the totalcomposition will be found suitable.

Similar considerations apply to the formulation of beverages. Generallyspeaking the compounds will find most utility in soft drinks, e.g. fruitsquashes, lemonade, cola etc., but may also be used in alcoholicbeverages. The amount of compound used will generally be in the range0.005 to 2.5% by weight based on the total composition.

Medicaments

Because of their cooling effect on the skin and on the mucous membranesof the mouth, throat and nose and of the gastrointestinal tract the3-substituted-p-menthanes may be used in a variety of oral medicines,nasal and throat sprays, and topical compositions, particularly where acounter-irritant is required. Generally speaking, these medicalpreparations, whether topical or ingestible proprietary or ethical, willcontain a pharmaceutically acceptable carrier, either liquid or solid, apharmaceutically active ingredient and into these preparations the3-substituted-p-menthanes of this invention can readily be incorporatedto provide a pleasant cooling effect on the skin, or other surfacetissues of the body, or in the mouth or gastrointestinal tract dependingon particular preparation and whether it is to be applied externally orinternally. A particular utility for the compounds of this invention isin the formulation of antacid and indigestion remedies, and especiallythose based on sodium bicarbonate, magnesium oxide, calcium or magnesiumcarbonate, aluminium or magnesium hydroxide or magnesium trisilicate. Insuch compositions the compound will usually be added in an amount offrom 0.01 to 0.5% by weight.

The 3-substituted-p-menthanes may also be included in oral analgesiccompositions e.g. with acetyl salicylic acid or its salts, and in nasaldecongestants e.g. those containing ephedrine.

Consumer products according to the invention are illustrated by thefollowing Examples in which all percentages are by weight.

EXAMPLE 1 Aerosol Shaving Soap

An aerosol shaving soap composition was formulated according to thefollowing recipe:

    ______________________________________                                        Stearic acid            6.3%                                                  Lauric acid             2.7                                                   Triethanolamine         4.6                                                   Sodium Carboxymethyl                                                          celluose                0.1                                                   Sorbitol                5.0                                                   Perfume                 0.4                                                   Water                   to 100                                                ______________________________________                                    

The composition was prepared by fusing the acids in water, adding thetriethanolamine, cooling and adding the other constituents. To themixture was then added 1.0%, based on the total composition ofN,N-dimethyl-p-menthane-3-carboxamide. The composition was then packagedin an aerosol dispenser under pressure of a butane propellant.

When used in shaving a fresh cool sensation was distinctly noticeable onthe face.

EXAMPLE 2 After Shave Lotion

An after shave lotion was prepared according to the following recipe bydissolution of the ingredients in the liquid and cooling and filtering:

    ______________________________________                                        Denatured Ethanol      75%                                                    Diethylphthalate       1.0                                                    Propylene Glycol       1.0                                                    Lactic Acid            1.0                                                    Perfume                3.0                                                    Water                  to 100%                                                ______________________________________                                    

Into two separate samples of the base lotion were added 2.0% by weightbased on the total composition of N-ethyl-p-menthane-3-carboxamide andN,N-dimethyl-p-menthane-3-carboxamide, each into a different one of thetwo samples.

When applied to the face a clearly noticeable cooling effect becameapparent after a short interval of time.

EXAMPLE 3 Toilet Water

A toilet water was prepared according to the following recipe:

    ______________________________________                                        Denatured ethanol      75.0%                                                  Perfume                5.0%                                                   Water                  to 100%                                                ______________________________________                                    

To the recipe was added 3.0%, based on the total composition ofN-p-menth-3-oylglycine methyl ester.

As with the after shave lotion, a cooling effect was clearly noticeableon the skin well after the termination of any cooling effectattributable to the evaporation of the alcoholic carrier.

EXAMPLE 4 Deodorant composition

A deodorant composition suitable for formulation and dispensing as anaerosol under pressure of a suitable propellant was formulated accordingto the following recipe:

    ______________________________________                                        Denatured ethanol      96.9%                                                  Hexachlorophene        2.0%                                                   Isopropyl myristate    1.0%                                                   Perfume                0.1%                                                   ______________________________________                                    

To the composition was added 1.3% by weight ofN-methyl-p-menthane-3-carboxamide. Application of the final compositiongave rise to a definte cooling sensation on the skin.

EXAMPLE 5 Hair Shampoo

Sodium lauryl ether sulphate, 10 g., was dispersed in 90 g. water in ahigh speed mill. To the dispersion was added 3.3% by weight ofN-(2-hydroxy-n-propyl)-p-menthane-3-carboxamide. When the hair is washedusing the shampoo, a fresh, cool sensation is noticed on the scalp.

EXAMPLE 6 Lipstick

0.6% by weight of N-(p-menth-3-oyl) glycine was incorporated into aproprietary lipstick by melting the lipstick, adding the compound, andallowing the lipstick to resoldify. When applied to the lips apersistent cooling effect is clearly noiticeable.

EXAMPLE 7 Solid Cologne

A solid cologne was formulated according to the following recipe:

    ______________________________________                                        Denatured ethanol      74.5%                                                  Propylene glycol       3.0%                                                   Sodium stearate        5.0%                                                   Perfume                5.0%                                                   Water                  to 100%                                                ______________________________________                                    

The sodium stearate was dissolved by stirring in a warm mixture of theethanol propylene glycol and water. To the solution was added theperfume and 3.0% of N-(2-hydroxy-n-propyl)-p-menthane-3-carboxamide andthe mixture then allowed to solidify into a waxy cake.

When applied to the forehead a very strong and long lasting coolingeffect is obtained.

EXAMPLE 8 Hair tonic

A hair tonic was formulated containing:

    ______________________________________                                        Denatured ethanol      84.5%                                                  Castor oil             14.0%                                                  Resorcinol             0.5%                                                   Perfume                1.0%                                                   ______________________________________                                    

The castor oil, resorcinol and perfume were dissolved in the ethanolcomponent and to the solution was added 2.0% of N-(p-menth-3-oyl)glycine methyl ester. When rubbed on the scalp a cooling effect isnoticed.

EXAMPLE 9 Eye Lotion

An eye lotion was prepared containing the following ingredients:

    ______________________________________                                        Witch Hazel     12.95%                                                        Boric Acid      2.00                                                          Sodium Borate   0.50                                                          Allantoin       0.05                                                          Salicylic Acid  0.025                                                         Chlorobutol     0.02                                                          Zinc Sulphate   0.004                                                         Water           to 100%                                                       ______________________________________                                    

To the formulation was added 0.003%, based on the total composition ofN-(2-hydroxyethyl)-p-menthane carboxamide. When used to bathe the eyes acool fresh sensation is apparent on the eyeball and eyelids.

EXAMPLE 10 Mouthwash

A concentrated mouthwash composition was prepared according to thefollowing recipe:

    ______________________________________                                        Ethanol           3.0%                                                        Borax             2.0                                                         Sodium bicarbonate                                                                              1.0                                                         Glycerol          10.0                                                        Flavourant        0.4                                                         Thymol            0.03                                                        Water             to 100%                                                     ______________________________________                                    

To the compositions was added 0.1% ofN-n-propyl-p-menthane-3-carboxamide.

When diluted with approximately 10 times its own volume of water andused to rinse the mouth a strong and long lasting cooling effect isobtained in the mouth.

EXAMPLE 11 Toothpaste

The following ingredients were mixed in a blender:

    ______________________________________                                        Dicalcium phosphate                                                                           48.0%                                                         Sodium lauryl sulphate                                                                        2.5                                                           Glycerol        24.8                                                          Sodium Carboxymethyl                                                          cellulose       2.0                                                           Citrus flavourant                                                                             1.0                                                           Sodium saccharin                                                                              0.5                                                           Water           to 100%                                                       ______________________________________                                    

Shortly before completion of the blending operation 0.5% by weight ofN-(p-menth-3-oyl) morpholine was added to the blender.

When applied as a toothpaste, a strong cooling effect is noticed in themouth.

This Example illustrates now the physiological cooling effect of thecompounds of this invention varies according to the locality ofapplication. When applies to the skin as an alcoholic solution, thecooling effect of N-(p-menth-3-oyl)morpholine is relatively weak. Whenapplied to the mucous membranes of the mouth the cooling effect is verypronounced.

EXAMPLE 12 Toothpicks

The tip of a wooden toothpick was impregnated with an alcoholic solutioncontaining N-ethyl-p-menthane-3-carboxamide in sufficient amount todeposit on the toothpick 0.01 mg. of the carboxamide. The impregnatedtoothpick was then dried. When placed on the tongue there is nodetectable taste, however, a distinct cooling effect is noticeable aftera short period of time.

EXAMPLE 13 Talcum Powder

A talcum powder was prepared by grinding together the following:

    ______________________________________                                        Low micron talc      90%                                                      Zinc stearate        5%                                                       Starch               5%                                                       ______________________________________                                    

In the course of grinding there was added 3.0% ofN-n-propyl-p-menthane-3-carboxamide. A talcum powder having a fresheningand cooling effect was obtained.

EXAMPLE 14 Soft Drink

A soft drink concentrate was prepared from the following recipe:

    ______________________________________                                        Pure orange juice 60%                                                         Sucrose           10                                                          Saccharin         0.2                                                         Orange flavouring 0.1                                                         Citric acid       0.2                                                         Sulphur dioxide   trace amount                                                Water             to 100%                                                     ______________________________________                                    

To the concentrate was added 0.02% ofN-(1,1-dimethyl-2-hydroxyethyl)-p-menthane-3-carboxamide.

The concentrate was diluted with water and tasted. An orange flavourhaving a pleasantly cool after-effect was obtained.

EXAMPLE 15 Alcoholic Beverage

N-(2-hydroxy-n-propyl)-p-menthane-3-carboxamide was added to aproprietary gin in an amount of 0.08%. When tasted a very strong coolingafter-effect is obtained in the mouth.

EXAMPLE 16 Boiled Sweet

99.5% sucrose and 0.5% citric acid were carefully fused together in thepresence of a trace of water. Just before casting the melt onto achilled plate 0.13% of N,N-dimethyl-p-menthane-3-carboxamide wererepidly stirred in. The melt was then cast. A boiled sweet resultedhaving a marked cooling effect on the mouth.

EXAMPLE 17 Mint Sweet

Water was added to icing sugar at 50° C to form a stiff paste. 0.05% ofN-ethyl-p-menthane-3-carboxamide was then stirred into a paste and themixture allowed to set. A soft sweet mass resulted having thecharacteristic cooling effect in the mouth of peppermint but without theminty flavour or odour.

EXAMPLE 18 Chewing Gum

Leaves of a proprietary chewing gum were leached in running water for168 hours to remove all water-soluble flavourants. At the end of theleaching operation the chewing gum base had no detectable minty odour orflavour. The chewing gum base was then kneaded with 5.0% ofN,N-bis(2-hydroxyethyl)-p-menthane-3-carboxamide. When compared with thewater-extracted chewing gum base, the final product showed nodistinguishable change in flavour but showed a marked cooling effect inthe mouth.

EXAMPLE 19 Ice Cream

A proprietary ice cream mixture was mixed in accordance with themanufactures instructions. Shortly before freezingN-p-menth-3-oyl-β-aminopropionic acid n-propyl ester was added in anamount of 0.05%. When sampled a cooling effect is noticeable whichpersists after the cooling effect attributable to the temperature of theice cream has disappeared.

EXAMPLE 20 Indigestion tablet

The following ingredients were ground together:

    ______________________________________                                        Magnesium carbonate                                                                             49.5%                                                       Sorbitol          49.4%                                                       Saccharin         0.1%                                                        Talc              1.0%                                                        ______________________________________                                    

Added to the mixture during grinding was 0.05% of N-ethyl-p-menthane-3-carboxamide. After mixing the mixture was pressed into 0.5 g tablets.

Taken by mouth and swallowed the tablets produces after a short intervalof time a noticeable cooling effect in the stomach.

EXAMPLE 21 Antiseptic Ointment

An ointment was prepared according to the following formulation:

    ______________________________________                                        Cetyltrimethyl ammonium bromide                                                                    4.0%                                                     Cetyl Alcohol        6.0%                                                     Stearyl Alcohol      6.0%                                                     White Paraffin       14.0%                                                    Mineral Oil          21.0%                                                    Water                to 100%                                                  ______________________________________                                    

The ingredients were mixed, warmed to 40° C and emulsified in a highspeed blender. Added to the mixture during blending was 0.5%N-(p-menth-3-oyl)glycine methyl ester.

The final ointment when applied to the skin gave rise to a markedcooling effect.

EXAMPLE 22 Antipruritic Ointment

The following ingredients were warmed together to form a homogenousmelt:

    ______________________________________                                        Methyl salicylate 50.0%                                                       White Beeswax     25.0%                                                       Anhydrous lanolin 25.0%                                                       ______________________________________                                    

To the melt was added 0.1% of N-(p-menth-3-oyl)glycine n-propyl esterand the mixture was then allowed to solidify. A soft ointment resultedhaving a soothing effect on the skin accompanied by a noticeable coolingeffect.

EXAMPLE 23 Analgesic tablet

Soluble aspirin (calcium acetylsalicylate) tablets were impregnated with0.05% of N-ethyl-p-menthane-3-carboxamide by absorption in the tablet ofa metered drop of an ethanolic solution of the carboxamide. When atablet was swallowed a quite noticeable cooling effect developed in thestomach after a short interval.

EXAMPLE 24 Cleansing Tissue

A cleansing liquid was prepared having the formulation:

    ______________________________________                                        Triethanolamine Lauryl sulphate                                                                        1.0%                                                 Glycerol                 2.0%                                                 Perfume                  .95%                                                 Water                    to 100%                                              ______________________________________                                    

To this liquid was added 1.0% of N-ethyl-p-menthane-3-carboxamide. Apaper tissue was then soaked in the liquid.

When the impregnated tissue was used to wipe the skin a fresh coolsensation developed on the skin after a short interval.

The experiment was repeated using 2.0% of N-3-hydroxypropyl-p-menthanecarboxamide in place of the N-ethyl compound with equally effectiveresults.

EXAMPLE 25 Water soluble Adhesive

A solution was made up containing 5% gum acacia in water. To thissolution was added 0.025% of N-ethyl-p-menthane-3-carboxamide. Thesolution was then coated on a label and allowed to dry. Licking thelabel to regain the tack prior to affixing the label to a substrate gavea pleasant cooling sensation on the tongue.

The above Examples illustrate the range of compounds and the range ofcompositions included within the present invention. However, they arenot to be taken as limiting the scope of the invention in any way.Numerous other compounds within the general formula will be equallysuitable for use in the compositions of Examples 1 - 25 and thephysiological cooling effect obtained with the compounds of theinvention will recommend their use in a wide variety of othercompositions where the cooling effect will be of value.

Toxicology and Dermatology

Toxicological studies of the compounds of this invention have shown thatthe compounds are substantially non toxic, LD₅₀ levels in mice beinghigher than 2g/kg. Enclosed patch tests on the skin, on both rabbits andhumans, have shown an extremely low level of allergic response even inpersons known to be extremely susceptible to skin allergies. Eye testson rabbits have also shown that the compounds of the invention aresubstantially free of ocular irritancy.

We claim:
 1. In a consumer product for application to or consumption bythe human body comprising a consumer product base and, as adjuvants insaid base, (i) at least one of the following: a flavourant, colourant,perfuming agent, surface active ingredient, antiseptic orpharmaceutically active agent, and (ii) an ingredient capable ofstimulating the cold receptors of the nervous system of the surfacetissues of the body in those parts of the human body with which theproduct comes in contact during use, the improvement which comprisesusing as the cold receptor stimulating ingredient an effective amount ofa substantially odourless cold receptor stimulating compound of theformula: ##STR2## wherein R' is hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, hydroxyalkyl, alkynyl, acyloxyalkyl, alkoxyalkyl,aminoalkyl, acylaminoalkyl, carboxyalkyl radical or an alkylcarboxyalkylradical of the formula -- C_(n) H_(2n) COOR'", wherein -- C_(n) H_(2n)is a straight or branched chain alkylene group in which n is an intergerfrom 1 to 6 and R'" is C₁ -C₈ alkyl, each of said radicals containing upto 25 carbon atoms; and R" is hydroxyl or an alkyl, cycloalkyl, alkenyl,cycloalkenyl, hydroxyalkyl, alkynyl, acyloxyalkyl, alkoxyalkyl,aminoalkyl, acylaminoalkyl, carboxyalkyl radical or an alkylcarboxyalkylradical of the formula -- C_(n) H_(2n) COOR'", wherein -- C_(n) H_(2n)is a straight or branched chain alkylene group in which n is an integerfrom 1 to 6 and R'" is C₁ -C₈ alkyl, each of said radicals containing upto 25 carbon atoms; with the proviso that when R' is hydrogen R" mayalso be an aryl radical of up to 10 carbon atoms selected from benzyland substituted phenyl wherein the substituents are selected from C₁ -C₄alkyl, hydroxy, C₁ -C₄ alkoxy, nitro and halogen.
 2. A product accordingto claim 1, wherein said compound is of the formula: ##STR3## where R'is hydrogen, C₁ -C₉ straight of branched chain alkyl, C₁ -C₉ straight orbranched chain hydroxyalkyl or aminoalkyl or a C₁ -C₄ acylatedderivative thereof, or --C_(n) H_(2n) COR'" or --C_(n) H_(2n) COOR'"where --C_(n) H_(2n) is a straight or branched chain alkylene group inwhich n is an integer of from 1-6 and R'" is hydrogen or C₁ -C₈ alkyland R", is an organic group as defined above for R', R' and R" being thesame or different.
 3. A product according to claim 1, which is apersonal care product comprising a topically administrable base and, asadjuvants in said base, (i) a perfuming agent, a surface active agent oran antiseptic agent, and (ii) said cold receptor stimulant.
 4. A productaccording to claim 1, which is a dentifrice comprising an orallyacceptable dentifrice base and, as adjuvants therein (i) a flavourant orantiseptic, and (ii) said cold receptor stimulant.
 5. A productaccording to claim 1, which is a toilet lotion comprising an aqueous,alcoholic or aqueous alcoholic base and, as adjuvants therein, (i) anantiseptic, perfuming agent, colourant or mixture thereof, and (ii) saidcold receptor stimulant.
 6. A product according to claim 7, which is acosmetic preparation comprising an oil-in-water emulsion base, and, asadjuvants in said base, (i) at least one of the following: anantiseptic, perfuming agent or colourant and (ii) said cold receptorstimulant.
 7. A product according to claim 1, which is a shavingpreparation comprising a foamable base containing a soap or syntheticsurfactant and, as adjuvants in said base, (i) a perfume or antisepticor a mixture thereof and (ii) said cold receptor stimulant.
 8. A productaccording to claim 1, which is an edible preparation comprising anedible base and, as adjuvants in said base (i) a flavourant and (ii)said cold receptor stimulant.
 9. A product according to claim 1, whichis a potable preparation comprising a potable base and, as adjuvants insaid base, (i) a flavourant and (ii) said cold receptor stimulant.
 10. Aproduct according to claim 1, which is a chewing gum containing achewing gum base and, as adjuvants therein, a flavourant and said coldreceptor stimulant.
 11. A product according to claim 1, which is apharmaceutical preparation comprising a pharmaceutically acceptablecarrier, and as adjuvants therein, (i) a pharmaceutically activecompound and (ii) said cold receptor stimulant.
 12. A method ofstimulating the cold receptors of the nervous system of the human bodywhich comprises applying thereto an effective amount of a cold receptorstimulating compound of the formula defined in claim 1.